Abstract: | Pancreatic stellate cells (PSCs) are activated during pancreatitis and promote pancreatic fibrosis by producing and secreting ECMs such as collagen and fibronectin. IL-1 has been assumed to participate in pancreatic fibrosis by activating PSCs. Activated PSCs secrete various cytokines that regulate PSC function. In this study, we have examined IL-1 secretion from culture-activated PSCs as well as its regulatory mechanism. RT-PCR and ELISA have demonstrated that PSCs express IL-1 mRNA and secrete IL-1 peptide. Inhibition of TGF- 1 activity secreted from PSCs by TGF- 1-neutralizing antibody attenuated IL-1 secretion from PSCs. Exogenous TGF- 1 increased IL-1 expression and secretion by PSCs in a dose-dependent manner. Adenovirus-mediated expression of dominant-negative (dn)Smad2/3 expression reduced both basal and TGF- 1-stimulated IL-1 expression and secretion by PSCs. Coexpression of Smad3 with dnSmad2/3 restored IL-1 expression and secretion by PSCs, which were attenuated by dnSmad2/3 expression. In contrast, coexpression of Smad2 with dnSmad2/3 did not alter them. Furthermore, inhibition of IL-1 activity secreted from PSCs by IL-1 -neutralizing antibody attenuated TGF- 1 secretion from PSCs. Exogenous IL-1 enhanced TGF- 1 expression and secretion by PSCs. IL-1 activated ERK, and PD-98059, a MEK1 inhibitor, blocked IL-1 enhancement of TGF- 1 expression and secretion by PSCs. We propose that an autocrine loop exists between TGF- 1 and IL-1 in activated PSCs through Smad3- and ERK-dependent pathways. fibrosis; cytokine; chronic pancreatitis |